The permeation of water through a cell membrane generally occurs slowly by way of diffusion into the lipid bilayer which is the main structure of the cell membrane. Recently, however, it was discovered that, in certain kinds of cells, water is transferred rapidly through the cell membrane, suggesting the involvement in the above phenomenon of some membrane protein selectively permeable to water. Thereafter, such membrane proteins of various kinds have actually been isolated. Such membrane proteins are designated as water channels. In this specification, the function of the above water channels which has selective permeation of water through the cell membrane is referred to as "water channel activity". The water channels may be permeable to water alone or permeable to not only water but also low-molecular-weight substances such as glycerol and urea.
As a membrane protein having such water channel activity, there have been isolated a group of membrane proteins known as aquapolins (AQPs). Furthermore, some aquapolin genes have so far been cloned, and aquapolins such as AQP1 through AQP5, FA-CHIP and AQP-.gamma.TIP have been discovered in mammals, amphibians, plants, etc. [cf. e.g. Akira Sasaki, Igaku no Ayumi (Advances in Medicine), vol. 173, No. 9, 1995].
P. Agre et al. reported, in Science (vol. 256, pp. 385 to 387, 1992) that Xenopus laevis oocytes in which the in vitro transcript RNA for CHIP28, the current designation of which is AQP1, had been introduced showed increased water permeability. In Science (vol. 264, pp. 92 to 95, 1994), B. A. van Oost et al. disclosed the amino acid sequence of human AQP2 and suggested that this should be involved in vasopressin-dependent urine concentration.
In Proc. Natl. Acad. Sci. USA (vol. 91, pp. 6269 to 6273, 1994), Ishibashi et al. disclosed the nucleotide sequence of the gene for renal collecting tubule-derived AQP3 and the amino acid sequence encoded thereof. Ishibashi et al. confirmed its water channel activity by injecting the AQP3 cRNA into Xenopus laevis oocytes and measuring the water permeability thereof. Ishibashi et al. reported that this AQP3 transported not only water but also nonionic small molecules such as urea and glycerol.
InProc. Natl. Acad. Sci. USA (vol.91, pp. 13052 to 13056, 1994), J. S. Jung et al. reported about the isolation of AQP4. This AQP4 is known to occur most abundantly in mammalian brains and have mercury resistance. In J. Biol. Chem. (vol. 270, pp. 1908 to 1912, 1995), S. Raina et al. who prepared rat salivary gland-derived AQP5 cDNA describe the nucleotide sequence of the cDNA and the amino acid sequence encoded thereby. S. Raina et al. cloned the cDNA by utilizing the occurrence of an NPA sequence and confirmed its function by observing that the cRNA enhances the water permeability of Xenopus laevis oocytes.
The aquapolin family mentioned above is considered to be involved in water metabolism in mammals and, for example, it has been confirmed that AQP2 is found only in the renal collecting tubule luminal membrane, which is indicative of its close association with the vasopressin-urea concentration system, and its involvement in renal diseases has become acknowledged. Therefore, such membrane proteins having water channel activity are of importance in any attempt to develop novel therapies for water-associated diseases.
Meanwhile, the expression of the aquapolin family mentioned above has been confirmed in such organs as kidney, brain, gall bladder, eye, intestine, salivary gland and bronchus but there is no report as yet about the occurrence of membrane proteins having water channel activity in other organs or tissues, particularly in adipose tissue.